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ABSTRACT: Immune status monitoring of transplant recipients could identify patients at risk of acute rejection, infection, and cancer, which are important sources of morbidity and mortality in these patients. The ImmuKnow assay provides an objective assessment of the cellular immune function of immunosuppressed patients. Inconclusive results concerning the ability of the ImmuKnow test to predict acute rejection and infection have raised concerns about the predictive value of ImmuKnow in liver transplant recipients. We conducted a systematic literature review to identify studies published up to March 2012 that documented the use of ImmuKnow for monitoring immune function in liver transplant recipients. The study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 score. We identified 5 studies analyzing ImmuKnow performance for infection and 5 studies analyzing ImmuKnow performance for acute rejection. The pooled sensitivity, specificity, positive likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 83.8% [95% confidence interval (CI) = 78.5%-88.3%], 75.3% (95% CI = 70.9%-79.4%), 3.3 (95% CI = 2.8-4.0), 14.6 (95% CI = 9.6-22.3), and 0.824 ± 0.034, respectively, for infection and 65.6% (95% CI = 55.0%-75.1%), 80.4% (95% CI = 76.4%-83.9%), 3.4 (95% CI = 2.4-4.7), 8.8 (95% CI = 3.1-24.8), and 0.835 ± 0.060, respectively, for acute rejection. Heterogeneity was low for infection studies and high for acute rejection studies. In conclusion, the ImmuKnow test is a valid tool for determining the risk of further infection in adult liver transplant recipients. Significant heterogeneity across studies precludes the conclusion that ImmuKnow identifies liver transplant patients at risk for rejection. Liver Transpl 18:1245-1253, 2012. © 2012 AASLD.
Liver Transplantation 06/2012; 18(10):1244-52. · 3.39 Impact Factor
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ABSTRACT: A patient receiving a liver graft needs to be treated with immunosuppressive drugs to avoid rejection. These kinds of drugs predispose the patient to the reactivation of latent infections such as tuberculosis (TB). Therefore, it is necessary to establish treatment regimens to prevent this. We retrospectively analyzed all consecutive patients undergoing liver transplantation (LT) at our center between January 1, 2000 and December 31, 2010. Latent tuberculosis infections (LTBIs) were diagnosed with positive tuberculin skin test results. After LT, infected patients were treated with isoniazid for 6 months; the treatment began soon after transplantation, and the patients were followed until the end of the study. During this period, 53 patients had LTBI data. All these patients were treated with isoniazid after LT. The median observation period after LT was 52 months (range = 12-129 months). No cases of TB reactivation were reported during follow-up. Only 4 patients presented alterations in liver enzymes related to this treatment, and they showed clear improvement after the treatment was stopped. None of these patients showed severe graft dysfunction. In conclusion, preventive isoniazid appears to be a safe drug for use in LTBI patients after LT. The treatment may be established just after LT without important graft dysfunction or severe consequences for the patient.
Liver Transplantation 05/2012; 18(9):1110-7. · 3.39 Impact Factor
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ABSTRACT: Water retention is a major clinical problem in patients with liver cirrhosis. The factors that predispose to water retention are poorly understood but may involve genetic factors. Recent research suggests that renal aquaporins may be a pathophysiological factor involved in this condition. Aquaporin-1 (AQP1) is expressed in the proximal tubule and aquaporin-2 (AQP2) in the renal collecting duct cells. The aim of our study was to investigate the distribution of single nucleotide polymorphisms (SNPs) of AQP1: rs1049305 (C/G) and AQP2: rs3741559 (A/G) and rs467323 (C/T) in 100 cirrhotic patients with ascites and to analyze their relationship with dilutional hyponatremia.
Genomic DNA was extracted from peripheral blood. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman SNP Genotyping Assays. The possible influence of rs1049305 (C/G) in AQP1 gene expression was evaluated by luciferase assays in vitro.
The allelic frequencies of the AQP1 gene were the following: CC = 15%; CG = 49%; GG = 36%. Patients with CC genotype had significantly lower plasma sodium concentration than those with CG or GG genotype. Luciferase assays showed that the rs1049305 (C/G) in the AQP1 gene functionally affected the expression level in vitro. In addition, we did not find any relationship between AQP2 SNPs observed and plasma sodium concentration.
Our results suggest that the rs1049305 (C/G, UTR3) AQP1 polymorphism could be involved in the genetic susceptibility to develop water retention in patients with liver cirrhosis.
Scandinavian journal of gastroenterology 07/2011; 46(10):1267-74. · 2.08 Impact Factor
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ABSTRACT: Pruritus is commonly associated with cholestatic disorders and shows wide interindividual variability. The presence of skin lesions due to scratching and the application of a visual analogue scale are useful for clinical evaluation. Although the pathophysiology of this entity is not well understood, advances have recently been made in understanding of the pruritoceptive neural pathway, which shares certain similarities with the nociceptive pathway, although there are other distinguishing characteristics such as the action of a specific neurotransmitter, GPR, on the first synapsis at the posterior horn of the spinal cord. Amongst the modulator systems of the pruritoceptive pathway is the action of the endogenous opioids. An increase of these opioids in cholestatic situations is the most widely accepted hypothesis for pruritus in these patients. Some treatments have proven efficacy in randomized clinical trials in patients with cholestatic disorders, such as anion exchange resins, rifampicin, opioid antagonists and ursodeoxycholic acid; the latter is especially useful in intrahepatic cholestasis of pregnancy.
Gastroenterología y Hepatología 10/2009; 33(4):313-22. · 0.73 Impact Factor
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ABSTRACT: We present the case of a 23-year-old man with fever of unknown origin, who developed acute liver failure 2 months after symptom onset, requiring an urgent liver transplantation. The diagnosis of adult-onset Still's disease was established after the reappearance of symptoms after transplantation, and high doses of corticosteroids were used to control disease activity. Subsequently, given the impossibility of tapering the steroid dose, interleukin-1 receptor blocking treatment was started with satisfactory outcome. We also review the published literature.
Gastroenterología y Hepatología 09/2009; 32(10):681-6. · 0.73 Impact Factor
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ABSTRACT: Interleukin-23 (IL-23) and T helper 17 (Th17) cells have been cast as major players in autoimmunity, but their role in transplantation immunity remains to be specified. The aim of our study was to investigate the time course of serum levels of IL-23 and IL-17 during hepatic allograft rejection. Serum levels of IL-23 and IL-17 were determined in 20 healthy subjects and 50 hepatic transplant recipients. These patients were divided into 2 groups: group I was composed of 15 patients with acute rejection, and group II was composed of 35 patients without acute rejection. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. The concentrations of IL-23 were similar for the rejection group and nonrejection group at early postoperative times. We observed a significant increase in serum IL-23 levels in the rejection group when a diagnosis of acute rejection had been established. Similarly to IL-23, at the diagnosis of acute rejection, the concentration of IL-17 was significantly higher in the rejection group versus the nonrejection group. The whole transplant group, including those with stable graft function, had higher serum levels of IL-23 and IL-17 than the controls during the entire postoperative period. In conclusion, IL-23 and IL-17 are up-regulated during acute hepatic rejection. These findings suggest a role for Th17 cells in human liver allograft rejection.
Liver Transplantation 07/2009; 15(6):629-33. · 3.39 Impact Factor
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Marta Martín-Llahí,
Marie-Noëlle Pépin,
Mónica Guevara,
Fernando Díaz,
Aldo Torre,
Alberto Monescillo,
Germán Soriano,
Carlos Terra, Emilio Fábrega,
Vicente Arroyo,
Juan Rodés,
Pere Ginès
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ABSTRACT: Hepatorenal syndrome is common in patients with advanced cirrhosis and constitutes a major problem in liver transplantation. There is no effective medical treatment for hepatorenal syndrome.
Forty-six patients with cirrhosis and hepatorenal syndrome, hospitalized in a tertiary care center, were randomly assigned to receive either terlipressin (1-2 mg/4 hour, intravenously), a vasopressin analogue, and albumin (1 g/kg followed by 20-40 g/day) (n = 23) or albumin alone (n = 23) for a maximum of 15 days. Primary outcomes were improvement of renal function and survival at 3 months.
Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases.
As compared with albumin, treatment with terlipressin and albumin is effective in improving renal function in patients with cirrhosis and hepatorenal syndrome. Further studies with large sample sizes should be performed to test whether the improvement of renal function translates into a survival benefit.
Gastroenterology 06/2008; 134(5):1352-9. · 11.68 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the rate of alcohol recidivism after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) and its influence on the allograft and patient survival, as well as the development of comorbidities and de novo cancers. The study was performed on 54 subjects previously analyzed and transplanted in our center for ALD, whose follow-up was prolonged to a mean of 99.2 (SD 31.7) months (range, 14-155). Medical records were reviewed, and data on alcohol consumption, therapeutic compliance, graft evolution, rejection, infections, comorbidities, rates of de novo malignancies and other clinical events, and survival were collected. Comparisons between groups were performed by the Fisher's exact test, and survival was assessed by the Kaplan-Meier method. Survival curves were compared using the Mantel-Cox statistic. The risk of death resulting from alcohol recidivism was analyzed with a Cox proportional hazards model. Fourteen patients who underwent transplantation for ALD (25.9%) returned to alcohol use between 5.0 and 86.9 months after OLT (median, 47.5). There was no significant association between the presence or absence of alcohol recidivism and the occurrence of graft rejection, infections, associated comorbidities after OLT, or compliance. The 5- and 10-year survival rates for patients with alcohol recidivism were 92.9% and 45.1%, respectively, compared with 92.4% and 85.5%, respectively, for patients without alcohol recidivism. These figures show significantly lower survival rates in recidivistic patients after 10 years (P < 0.01, Mantel-Cox). The fact that patients who resumed alcohol consumption have a worse 10-year survival rate might be attributed to a higher frequency of deaths, primarily from cancer and cardiovascular events.
Liver Transplantation 04/2005; 11(4):420-6. · 3.39 Impact Factor
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ABSTRACT: The mechanisms leading to osteoporosis in alcoholic liver disease remain poorly understood. Recently identified soluble circulating osteoprotegerin (OPG), is the osteoclastogenesis inhibitory factor. It acts as a decoy receptor for osteoclast activating factor, receptor activator of nuclear factor-kappaB ligand (RANKL), and impairs osteoclast function. The aim of our study was to investigate the OPG/RANKL system in alcoholic cirrhotic patients and their correlation with biochemical marker of bone turnover.
Serum OPG, RANKL, osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX-I), bone alkaline phosphatase activity (bALP), and urinary hydroxyproline were measured in 30 patients with alcoholic cirrhosis, and in 20 age- and sex-matched healthy controls.
OPG levels were significantly increased in patients with alcoholic cirrhosis compared with healthy subjects (5.9 pmol/l, range 2.7-9.0 vs 4.1 pmol/l, range 1.2-6.6; P < 0.001). RANKL levels were significantly higher in patients with cirrhosis (0.48 pmol/l, range 0.01-1.34) than in healthy subjects (0.11 pmol/l, range 0.01-0.90). There was a positive correlation between serum OPG and RANKL (r = 0.37; P < 0.001), bALP (r = 0.66; P < 0.001) and urinary hydroxyproline (r = 0.51; P < 0.05) but not with OC and CTX-I.
OPG might partly represent a compensating mechanism to the negative balance of bone remodelling in patients with alcoholic cirrhosis.
Liver international: official journal of the International Association for the Study of the Liver 04/2005; 25(2):305-10. · 3.82 Impact Factor
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ABSTRACT: The enduring shortfall of organ donors has inspired the widespread utilization of hepatic allografts from donors with hepatitis B core antibodies in spite of the potential risk of transmitting hepatitis B virus (HBV) infection to the recipient. Here we report a protocol of naive recipients receiving livers from hepatitis B core antibody-positive donors. From November, 1999 to March, 2002, 77 liver transplantations were performed in 73 patients at our institution, 7 of whom received livers from hepatitis B core antibody-positive donors. All recipients received 10,000 U/d of intravenous HBIg for 7 days and 100 mg/d of lamivudine until we could obtain the HBV-DNA from the donor samples (serum and liver tissue). If the results of the HBV-DNA from the donor samples were positive, the patient would continue with prophylaxis and if they were negative we would finish the combined prophylaxis. After transplantation, HBV serologic markers and HBV-DNA by polymerase chain reaction (PCR) in serum and lymphocytes were tested in the recipients on the seventh, fifteenth, thirtieth, and ninetieth days as well as every 3 months after transplantation. All seven donor organs were negative for HBV-DNA in serum and liver tissue. Thus, we stopped the combined prophylaxis in all recipients (range, 7 to 10 days). None of the 7 patients developed de novo HBV infection over the 3-year study period (range, 9 to 36 months). Our approach is reasonably safe, and it appears to be very effective in the prevention of de novo HBV infection after liver transplantation.
Liver Transplantation 10/2003; 9(9):916-20. · 3.39 Impact Factor
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ABSTRACT: The aim of this study was to examine the possible relationship between the plasma levels of leptin and tumor necrosis factor (TNF)-alpha and the stage of hepatic fibrosis in a cohort of patients with chronic hepatitis C. Leptin and TNF levels were measured by RIA in 135 patients and in 75 age- and sex-matched controls. Liver disease was evaluated by the stage of fibrosis and the extent of inflammatory infiltrate in the liver biopsy. Leptin levels correlated with BMI values in healthy controls and in patients with chronic hepatitis C (men, r = 0.61, P = 0.0001; women, r = 0.68, P = 0.003). Leptin levels increased as hepatic fibrosis stage progressed both in male and in female patients (P < 0.001); also, TNF levels were higher in patients with an advanced stage of fibrosis (P = 0.006). In these patients, levels of leptin increased according to the progression of the stage of fibrosis; these data suggest that leptin may play a role in the regulation of hepatic fibrosis.
Digestive Diseases and Sciences 07/2002; 47(7):1604-10. · 2.12 Impact Factor
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ABSTRACT: Background. Inducible adhesion molecules are involved in cell-mediated allograft rejection. In addition, the endothelium is the main target of this process. This study investigated, whether soluble (s) forms of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) are elevated during cellular rejection and whether hyaluran is a useful marker of endothelial function in liver transplantation.
Methods. Serum levels of sICAM-1, sVCAM-1, and hyaluran were determined in 24 controls and 27 hepatic transplant recipients. These patients were divided in two groups: group I, 14 patients without rejection; and group II, 13 patients with rejection. Samples were collected on day 1 and 7 after transplantation, on the day of liver biopsy, and after treatment of the rejection.
Results. We found a significant increase in sICAM-1 levels in the postoperative period in the rejection group compared with the non rejection group. It persisted significantly elevated until the diagnosis of rejection was made. In contrast, sVCAM-1 was only significantly elevated in the rejection group when diagnosis of rejection was evident. Hyaluran levels were also significantly elevated in the rejection group at diagnosis of rejection. We noticed a significant decline in sICAM-1, sVCAM-1, and hyaluran levels after successful treatment of rejection. In addition, we observed in the non-rejection group a stable lower levels of hyaluran during the entire postoperative period.
Conclusions. The release of circulating adhesion molecules is a prominent feature coinciding with the first episode of hepatic rejection. Differential patterns of sICAM-1 and sVCAM-1 exist during rejection. In addition, hyaluran levels may be a sensitive marker of liver endothelial cell function in the postoperative period of liver transplantation.
Transplantation 02/2000; 69(4):569-573. · 4.00 Impact Factor
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Transplantation 06/1995; 59(12):1748-1751. · 4.00 Impact Factor
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ABSTRACT: The precise mechanism that leads to accelerated bone resorption in the early post-transplant period remains unclear. Recent data suggest that osteoprotegerin (OPG) and its ligand receptor activator of nuclear factor-kappaB ligand (RANKL) constitute a novel cytokine system that can influence the function of both bone and immune cells. The aim of our study was to assess OPG and RANKL concentrations in the early post-operative period of liver transplantation.
Serum OPG and RANKL levels were measured in 30 patients who underwent liver transplantation at 1, 7 and 14 d post-operatively. These values were compared with 22 age- and sex-matched healthy controls. Plasma sodium, creatinine, aspartate-aminotransferase, alanine-amino transferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time, tacrolimus and cyclosporine levels were measured in each patient.
We found a significant increase in OPG levels in the early post-operative period compared with the control group: day 1 (10.42 pmol/L, range 3.80-17.50 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001), day 7 (6.90 pmol/L, range 3.00-15.30 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001) and day 14 (5.76 pmol/L, range 2.60-10.70 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.001). Similarly, serum RANKL levels were significantly higher than in the control group in this period, day 1 (0.123 pmol/L, range 0.010-0.420 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.02), day 7 (0.236 pmol/L, range 0.010-0.720 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.0004) and day 14 (0.137 pmol/L, range 0.010-0.520 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.007). No correlation was found between OPG levels and RANKL, ischemic times, liver function tests, albumin, sodium or creatinine concentrations and tacrolimus or cyclosporine levels.
A significant amount of OPG and RANKL is released in the early post-transplant period of liver transplantation. This might be explained by an activation of the immune system caused by the allograft. Therefore, the RANKL/OPG system may be involved in the pathophysiological evolution of transplantation osteoporosis.
Clinical Transplantation 20(3):383-8. · 1.67 Impact Factor
